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Proliferation of aneuploid human cells is limited by a p53-dependent mechanism.

Thompson SL, Compton DA - J. Cell Biol. (2010)

Bottom Line: However, the relationship of aneuploidy and CIN is unclear because the proliferation of cultured diploid cells is compromised by chromosome missegregation.The mechanism for this intolerance of nondiploid genomes is unknown.These data fit with the concordance of aneuploidy and disruption of the p53 pathway in many tumors, but the presence of aneuploid cells in some normal human and mouse tissues indicates that there are known exceptions to the involvement of p53 in aneuploid cells and that tissue context may be important in how cells respond to aneuploidy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.

ABSTRACT
Most solid tumors are aneuploid, and it has been proposed that aneuploidy is the consequence of an elevated rate of chromosome missegregation in a process called chromosomal instability (CIN). However, the relationship of aneuploidy and CIN is unclear because the proliferation of cultured diploid cells is compromised by chromosome missegregation. The mechanism for this intolerance of nondiploid genomes is unknown. In this study, we show that in otherwise diploid human cells, chromosome missegregation causes a cell cycle delay with nuclear accumulation of the tumor suppressor p53 and the cyclin kinase inhibitor p21. Deletion of the p53 gene permits the accumulation of nondiploid cells such that CIN generates cells with aneuploid genomes that resemble many human tumors. Thus, the p53 pathway plays an important role in limiting the propagation of aneuploid human cells in culture to preserve the diploid karyotype of the population. These data fit with the concordance of aneuploidy and disruption of the p53 pathway in many tumors, but the presence of aneuploid cells in some normal human and mouse tissues indicates that there are known exceptions to the involvement of p53 in aneuploid cells and that tissue context may be important in how cells respond to aneuploidy.

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Inhibition of p38 stress kinase but not MAPK allows proliferation of aneuploid cells. (A and B) HCT116 cells with wild-type p53 and RPE1 cells were treated as described in Fig. 5. After shake-off, cells were grown in the presence of p38 inhibitor (SB203580; A) or MAPK inhibitor (PD98059; B) for the remainder of the experiment. For each time point/condition, 600 nuclei were counted per chromosome. Bars represent the mean percent deviation from the modal chromosome number, and error bars show SEM. *, P < 0.05; χ2 test.
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fig6: Inhibition of p38 stress kinase but not MAPK allows proliferation of aneuploid cells. (A and B) HCT116 cells with wild-type p53 and RPE1 cells were treated as described in Fig. 5. After shake-off, cells were grown in the presence of p38 inhibitor (SB203580; A) or MAPK inhibitor (PD98059; B) for the remainder of the experiment. For each time point/condition, 600 nuclei were counted per chromosome. Bars represent the mean percent deviation from the modal chromosome number, and error bars show SEM. *, P < 0.05; χ2 test.

Mentions: It has recently been shown that cell cycle arrest is mediated by the p38 stress kinase in response to disruption of the cytoskeleton (Mikule et al., 2007; Uetake et al., 2007), so we tested whether the p38-dependent stress pathway participated in cell cycle delay in cells after chromosome missegregation. We induced chromosome missegregation in HCT116 cells as well as in immortalized but nontransformed RPE1 cells by using the monastrol washout strategy. Using FISH with chromosome-specific probes, we then determined the chromosome content of the populations as they propagated in the presence of either the p38 inhibitor SB203580 or the MAPK inhibitor PD98059 (Fig. 6). As expected, the percentage of aneuploid cells in populations of both HCT116 and RPE1 cells increased immediately after monastrol washout. In the presence of the MAPK inhibitor, the percentage of aneuploid cells in both populations declined to background levels over time (Fig. 6 B). In contrast, the percentage of aneuploid cells in both populations remained elevated in the presence of the p38 inhibitor (Fig. 6 A). As p38 is known to directly phosphorylate p53 in response to cellular stress (Bulavin et al., 1999), these data suggest that a stress response can induce a p53-dependent pathway to pause the cell cycle in response to chromosome missegregation.


Proliferation of aneuploid human cells is limited by a p53-dependent mechanism.

Thompson SL, Compton DA - J. Cell Biol. (2010)

Inhibition of p38 stress kinase but not MAPK allows proliferation of aneuploid cells. (A and B) HCT116 cells with wild-type p53 and RPE1 cells were treated as described in Fig. 5. After shake-off, cells were grown in the presence of p38 inhibitor (SB203580; A) or MAPK inhibitor (PD98059; B) for the remainder of the experiment. For each time point/condition, 600 nuclei were counted per chromosome. Bars represent the mean percent deviation from the modal chromosome number, and error bars show SEM. *, P < 0.05; χ2 test.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2819684&req=5

fig6: Inhibition of p38 stress kinase but not MAPK allows proliferation of aneuploid cells. (A and B) HCT116 cells with wild-type p53 and RPE1 cells were treated as described in Fig. 5. After shake-off, cells were grown in the presence of p38 inhibitor (SB203580; A) or MAPK inhibitor (PD98059; B) for the remainder of the experiment. For each time point/condition, 600 nuclei were counted per chromosome. Bars represent the mean percent deviation from the modal chromosome number, and error bars show SEM. *, P < 0.05; χ2 test.
Mentions: It has recently been shown that cell cycle arrest is mediated by the p38 stress kinase in response to disruption of the cytoskeleton (Mikule et al., 2007; Uetake et al., 2007), so we tested whether the p38-dependent stress pathway participated in cell cycle delay in cells after chromosome missegregation. We induced chromosome missegregation in HCT116 cells as well as in immortalized but nontransformed RPE1 cells by using the monastrol washout strategy. Using FISH with chromosome-specific probes, we then determined the chromosome content of the populations as they propagated in the presence of either the p38 inhibitor SB203580 or the MAPK inhibitor PD98059 (Fig. 6). As expected, the percentage of aneuploid cells in populations of both HCT116 and RPE1 cells increased immediately after monastrol washout. In the presence of the MAPK inhibitor, the percentage of aneuploid cells in both populations declined to background levels over time (Fig. 6 B). In contrast, the percentage of aneuploid cells in both populations remained elevated in the presence of the p38 inhibitor (Fig. 6 A). As p38 is known to directly phosphorylate p53 in response to cellular stress (Bulavin et al., 1999), these data suggest that a stress response can induce a p53-dependent pathway to pause the cell cycle in response to chromosome missegregation.

Bottom Line: However, the relationship of aneuploidy and CIN is unclear because the proliferation of cultured diploid cells is compromised by chromosome missegregation.The mechanism for this intolerance of nondiploid genomes is unknown.These data fit with the concordance of aneuploidy and disruption of the p53 pathway in many tumors, but the presence of aneuploid cells in some normal human and mouse tissues indicates that there are known exceptions to the involvement of p53 in aneuploid cells and that tissue context may be important in how cells respond to aneuploidy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.

ABSTRACT
Most solid tumors are aneuploid, and it has been proposed that aneuploidy is the consequence of an elevated rate of chromosome missegregation in a process called chromosomal instability (CIN). However, the relationship of aneuploidy and CIN is unclear because the proliferation of cultured diploid cells is compromised by chromosome missegregation. The mechanism for this intolerance of nondiploid genomes is unknown. In this study, we show that in otherwise diploid human cells, chromosome missegregation causes a cell cycle delay with nuclear accumulation of the tumor suppressor p53 and the cyclin kinase inhibitor p21. Deletion of the p53 gene permits the accumulation of nondiploid cells such that CIN generates cells with aneuploid genomes that resemble many human tumors. Thus, the p53 pathway plays an important role in limiting the propagation of aneuploid human cells in culture to preserve the diploid karyotype of the population. These data fit with the concordance of aneuploidy and disruption of the p53 pathway in many tumors, but the presence of aneuploid cells in some normal human and mouse tissues indicates that there are known exceptions to the involvement of p53 in aneuploid cells and that tissue context may be important in how cells respond to aneuploidy.

Show MeSH
Related in: MedlinePlus